Strontium phosphate microparticle for radiological imaging and therapy

ABSTRACT

This invention relates to strontium-phosphate microparticles that incorporate radioisotopes for radiation therapy and imaging.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.12/883,827 filed Sep. 16, 2010 and issued Oct. 21, 2014 as U.S. Pat. No.8,865,123.

FIELD OF THE INVENTION

The field of the present invention is radiomicroparticles for medicaltherapy and imaging, and particularly radioactive strontium phosphatemicroparticles for radiological imaging and radioisotope therapy.

BACKGROUND

In the treatment of patients with certain kinds of cancer or rheumatoidarthritis, methods are known in which radioactive particles areintroduced intravascularly to a tumor site (radioembolization) orlocally into the synovial fluid in a joint in order to trap theradioactive particle at a particular site for its radiation effect.Similar methods are used for imaging parts of the body, organs, tumors,and so forth.

According to this technique, a quantity of the radioactive particles areinjected into a localized area of the patient to be imaged and/ortreated. For imaging, gamma emitting materials are commonly used tolabel carriers that provide imaging of a tissue area, tumor or organ.Some of these carriers have a specific affinity for certain bindingsites or biochemical targets allowing target specific or locationspecific uptake of the labelled carrier.

Radiological imaging of various tissues in the human body is commonlyaccomplished using Technetium-99m, typically by single photon emissioncomputed tomography (SPECT). ⁹⁹ ^(m) -Tc is a well-known radioactiveisotope used for radiodiagnostics and imaging such as SPECT. It emitsdetectable low level 140 keV gamma rays, has a half-life of 6 hours anddecays to Tc-99 in 24 hours (93.7%). It is used for imaging and functionstudies of the brain, myocardium, thyroid, lungs, liver, gallbladder,kidneys, bone, blood, and tumors. It is reported to be used in over 20million diagnostic nuclear medicine procedures each year. Positronemission tomography (PET) employs radionuclides that emit positrons, abeta-like nuclear particle that travels a few millimetres from itsnucleus, collides with an electron leading to annihilation resulting increating two photons of 511 KeV that travel in 180° opposite direction.The PET imaging system captures and registers the photons arising fromthe collision precisely at the same time thereby providing exceptionalimaging sensitivity. PET imaging has become a valuable diagnosticimaging procedure, particularly in the oncology area and it has beenreported that in the US approximately two million PET scans areperformed annually. Radioisotopes commonly employed for PET imaginginclude fluorine-18 (¹⁸F) that has a half-life of 109.8 minutes andgallium-68 (⁶⁸Ga) that has a half-life of 68 minutes.

Targeted radiation therapy using microparticles or microspheres is alsoa well-developed field radioisotope therapy. Radionuclides such asYttrium-90 and Holmium-166 are commonly used radioactive beta emittersin microsphere radiotherapy. Polymer microspheres such as albumin,poly-lactic acid derivatives, and so forth, and glass microspheres, areboth generally known in the medical arts for use in delivering bothpharmaceuticals and radiopharmaceuticals to specific tissue sites. Thesemicrospheres are usually provided preloaded with a single radionuclideand so lack the flexibility to control dose or radionuclide depending onthe patient's needs. Further, when radio micro particles are prepared inbulk, off-site by third party providers, the selection of radionuclideavailable for use may be limited, by the time involved in preparationand delivery.

However, a need remains for a radioactive microparticle for delivery ofone or more radiopharmaceuticals and which have characteristics whichwill permit the microparticles to be suitable for injection into apatient for localized imaging or therapy.

BRIEF SUMMARY OF THE INVENTION

The invention provides a radio microparticle comprising crystallinestrontium phosphate and at least one radioisotope suitable for radioimaging and/or radiotherapy bonded or adsorbed to the surface thereof.

The radio microparticle of the present invention is prepared by reactinga strontium-containing borate glass microparticle with a phosphatesolution in amounts and for a sufficient time under suitable conditions(such as time, temperature, phosphate concentration etc.) to convert atleast a portion strontium-containing borate glass at the surface tocrystalline strontium phosphate, and bonding at least one radioisotopesuitable for radio imaging and/or radiotherapy to the surface of saidmicroparticle. This results in radiopaque, porous particles capable ofbeing loaded with one or more radioisotopes and therefore being able todeliver radiation in a dose suitable for radiotherapy, or depending onthe isotope chosen, for use in radiodiagnostics.

There is also provided a strontium phosphate radiomicroparticle, made bythe process comprising:

a. reacting a strontium-containing borate glass microparticle with aphosphate solution such as to convert at least a portion of thestrontium-containing borate glass microparticle to strontium phosphate;and

b. bonding or adsobing at least one radioisotope suitable forradioimaging and/or radiotherapy to said microparticle.

In other preferred embodiments, there are provided additional featuresavailable singularly and in combination.

In other preferred embodiments, there are provided additional featuresavailable singularly and in combination.

In one preferred process, there is provided wherein thestrontium-containing borate glass microparticle is a microsphere havinga diameter of about 5, 10 or 20 um to about 1000 μm.

In one preferred process, there is provided wherein the strontiumphosphate microparticle has a surface area of about 90 square meters pergram or greater. The surface area may be up to about 200 square metersper gram or greater. Preferably the surface area is between about 90 toabout 200 square meters per gram. In one preferred process, there isprovided wherein the at least one radioisotope is a therapeutic alpha orbeta-emitting radioisotope; and/or wherein the at least one radioisotopeis a diagnostic proton or gamma-emitting radioisotope; and/or whereinthe at least one radioisotope is a combination of a therapeutic alpha orbeta-emitting radioisotope and a diagnostic proton or gamma-emittingradioisotope.

In one preferred process, there is provided wherein the step of bondingor adsorbing said at least one radioisotope suitable for radioimagingand/or radiotherapy to the strontium phosphate microparticle is preparedin situ in a clinical setting by mixing just prior to the time ofadministration to a patient said strontium phosphate microparticle withthe at least one radioisotope suitable for radioimaging and/orradiotherapy. Thus the step of bonding the radioisotope to the strontiumphosphate microparticle may be carried out just prior to the time ofadministration to a patient (e.g. within 6, 12 or 24 hrs)

In one preferred process, there is provided wherein the at least oneradioisotope is Technetium-99m; and/or wherein the at least oneradioisotope is selected from the group consisting of Technetium-99m,Indium-111 Lutetium-177, Samarium-153, Yttrium-90, Gallium-68,Fluorine-18 and combinations thereof.

In another preferred embodiment, there is provided a strontium phosphateradiomicroparticle made according to the process described herein.

In one preferred radiomicroparticle, there is provided wherein the atleast one radioisotope comprises at least two different radioisotopes;and/or wherein the at least one radioisotope comprises at least threedifferent radioisotopes.

In another preferred embodiment, there is provided a method ofadministering strontium-phosphate radiomicroparticles to a patient inneed thereof, comprising locally delivering (for example by catheter orsuitable intravenous injection) to a tissue target or organ of thepatient a composition comprising strontium-phosphate microparticles withat least one radioisotope bonded or adsorbed thereto and aphysiologically acceptable carrier.

In other preferred methods, there are provided additional featuresavailable singularly and in combination.

In one preferred method, there is provided wherein the at least oneradioisotope is a radiodiagnostic agent; and/or wherein the at least oneradioisotope is a radiotherapeutic agent; and/or wherein the at leastone radioisotope comprises a radiodiagnostic agent and aradiotherapeutic agent.

In one preferred method, there is provided wherein the at least oneradioisotope comprises at least two different radioisotopes; and/orwherein the at least one radioisotope comprises at least three differentradioisotopes.

In one preferred method, there is provided wherein the at least oneradioisotope is technetium-99m; and/or wherein the at least oneradioisotope is selected from the group consisting of Technetium-99m,Indium-111, Yttrium-90, Lutetium-177, Samarium-153, Gallium-68,Fluorine-18 and combinations thereof; and/or wherein the compositionalso contains an additional radiotherapeutic agent.

In one preferred method, there is provided wherein the tissue target ororgan is selected from the group consisting of: brain, myocardium,thyroid, lung, liver, spleen, gall bladder, kidney, bone, blood, andhead and neck tumor, prostate, breast, ovarian and uterine. In onepreferred method, there is provided wherein the strontium phosphatemicroparticles with at least one radioisotope are prepared in situ in aclinical setting by mixing just prior to the time of administration to apatient said strontium phosphate microparticle with the at least oneradioisotope suitable for radioimaging and/or radiotherapy.

In another preferred embodiment, there is provided a method of obtaininga radiologic image of a tissue or organ of a patient, comprisingadministering (e.g. by catheter or suitable intravenous injection) to atissue target or organ of the patient a composition comprisingstrontium-phosphate microparticles with at least one radiodiagnosticagent bonded or adsorbed thereto in a physiologically acceptablecarrier, and obtaining the radiologic image of the tissue or organ ofthe patient, such as by imaging the photons or gamma radiation emittedby the radiodiagnostic agent using a suitable radionuclide imagingtechnique. The imaging technique may, for example be SPECT or PET.

Additional features of this method include: wherein the at least oneradioisotope is a radiodiagnostic agent; wherein the radiodiagnosticagent is Technetium-99m; and wherein the tissue target or organ isselected from the group consisting of: brain, myocardium, thyroid, lung,liver, spleen, gall bladder, kidney, bone, blood, and head and necktumor, prostate, breast, and uterine.

There is also provided microparticles, particularly microspheres,comprising crystalline strontium phosphate and having a diameter ofbetween 5 and 1000 um (preferably 5, 10 or 20 to 200 um). Preferablysuch microspheres have a surface area of 90 meters square per gram orgreater

In other preferred embodiments, there are provided additional featuresavailable singularly and in combination, including: wherein thestrontium-containing borate glass microparticle is a microsphere;wherein the strontium-containing borate glass microparticle is fullyconverted to a strontium phosphate microparticle through to theinterior, or wherein it is partially converted to create a porous layerover an unconverted glass core; wherein the strontium-containing borateglass microparticle is between about 20 and about 40 microns indiameter; wherein the strontium-containing borate glass microparticle isbetween about 5 um and about 1000 um in diameter; wherein the strontiumphosphate microparticle is amorphous or crystalline; wherein thestrontium phosphate microparticle is a microsphere; wherein thestrontium phosphate microsphere or strontium phosphate portion of themicrosphere is porous; and wherein the strontium-containing borate glassmicrosphere is fully converted to a strontium phosphate microparticle.The strontium containing biorate glass is converted to a mineral of theBevolite Sr₁₀ (PO₄)₆ (OH)₂ type. In some embodiments, thestrontium-containing borate glass microparticle may be substantiallycalcium-free.

In another preferred embodiment, the at least one radioisotope is anyapproved radiopharmaceutical available to nuclear medicinepractitioners.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the conversion of a strontium containing borate glassmicrosphere into a crystalline strontium phosphate microsphere

FIG. 2 shows the up-take of 90Y from a solution of 90Yttrium chlorideinto strontium phosphate microspheres of the invention over a period of30 minutes.

DETAILED DESCRIPTION OF THE INVENTION

This application is a continuation-in-part of application Ser. No.12/883,827 filed Sep. 16, 2010 and issued Oct. 21, 2014 as U.S. Pat. No.8,865,123, the entire disclosure of which is expressly incorporatedherein by reference.

In accordance with the present invention, novel porous strontiumphosphate microparticle carriers have been devised for use in theimaging and/or treatment of certain tumor bearing tissue, rheumatoidarthritis, or other diseases where nuclear medicine imaging or treatmentis indicated. These carriers constitute microparticles that comprise aporous strontium-phosphate material having one or moreradiopharmaceuticals bound or adsorbed to the surface. Radiodiagnosticgamma or proton emitting agents and radiotherapeutic alpha or betaemitting agents are contemplated.

Overview

The strontium phosphate radiomicroparticle of the present invention ismade by reacting a strontium-containing borate glass microparticle witha phosphate solution in amounts and for a sufficient time under suitableconditions to convert the strontium-containing borate glassmicroparticle to a strontium phosphate microparticle, and bonding atleast one radioisotope suitable for radioimaging and/or radiotherapy ina mammal to said strontium phosphate microparticle.

The phosphate solution conversion process converts a solid strontiumborate glass into a porous strontium phosphate material. Bymanufacturing a non-radioactive solid strontium-containing borate glassmicroparticle of a specific diameter, the conversion results in a porousstrontium phosphate microparticle of a specific diameter. Due to thesubstantially thorough chemical action of the phosphate solution on theborate glass, a substantially pure porous strontium phosphate materialhaving a high surface area is achieved in the location where thephosphate solution has reacted with the borate glass.

The porosity of the resulting strontium phosphate material and thecontrollable size and number of the microparticles provide an excellentdelivery platform for delivering compounds of interest to specificlocations. Thus, the process of manufacturing of the microsphere hasbeen divorced from the process of adding the radiolabel orradiotherapeutic. This provides nuclear medicine professionals theability to control the radiodiagnostic and radiotherapeutic regimen byallowing, in the clinical setting, at or near the time of delivery, thedecision of the type and quantity of radiopharmaceutical(s) to beincorporated into the delivery vehicle.

Advantages

Some of the advantages provided by this approach include: the ability toadsorb a radioisotope or combination of radioisotopes onto a porousmicroparticle, the ability to customize dose to the patient, customizeimaging of the tissue, reducing time-related degradation of theactivated radiopharmaceutical, and reducing exposure to medicalpersonnel.

An additional advantage provided by this approach includes an increasein radio-opacity which provides clearer radiographic images due to theuse of strontium phosphate rather than calcium apatite.

A further advantage provided by this approach includes the ability toblend two or more different radioisotopes. Further, this allows for thetherapy to be able to change over time, or be customized to a particularset of circumstances.

A further advantage is the ability to use radioisotopes that have ashort half life and to avoid using microparticle manufacturing processesthat would vaporize certain radioisotopes such as Technetium andRhenium.

Porosity

Importantly, the strontium phosphate microparticles achieve a porosity,or surface area, that allows for a significant amount of radioisotope tobe bound. It is contemplated that surface area values of 90 squaremeters per gram or greater are within the scope of the presentinvention. The surface area may be up to 200 meters squared per gram orgreater. The surface area is preferably between 90 and 200 meterssquared per gram.

Significantly, prior art attempts using calcium apatite to create themicroparticles have provided much lower surface area values of only 40sq. meters per gram, or less. Further, these calcium-only microparticlesdemand complex manufacturing that includes a two-step process to adsorbthe isotope requiring a binder, a heating step that destroys the surfacearea, and chemical precipitation.

These radioactive substantially spherical strontium phosphateradiomicroparticles are made by reacting a pre-made strontium-containingborate glass microparticle with a phosphate solution in amounts and fora sufficient time under suitable conditions to convert, partially orfully, the strontium-containing borate glass microparticle to anamorphous or crystalline strontium phosphate microparticle. Once theglass has been converted and the porous material is made, aradioisotope-bearing radiopharmaceutical is then adsorbed or bonded tothe substantially pure strontium phosphate microparticle and is thensuitable for radioimaging and/or radiotherapy in a mammal.

Phosphate Conversion

The phosphate solution conversion process converts a solid strontiumborate glass microparticle into a porous strontium phosphate materialthat can be either amorphous or crystalline, but is preferablycrystalline. Amorphous strontium phosphate converts to crystallinestrontium phosphate with time. The glass can be converted completelythus forming a completely porous or even hollow microparticle. The glasscan also be partially converted thus resulting in a glass core and anouter porous strontium phosphate layer, which surrounds the core and towhich radioisotopes may be bound or adsorbed, as described herein. Thestrontium-containing borate glass microparticle may be fully convertedto a strontium phosphate microparticle, or it may be partially convertedto create a layer comprising strontium phosphate covering the surface ofthe particle and an unconverted strontium containing borate glass core.Preferably the strontium phosphate containing surface layer is at leastabout 0.5 um thick, but it may be at least 1, 2, 3, 4, 5, 7 or 10 umthick depending on the properties required, such as binding capacity,density etc. The conversion of the borate glass is performed by exposingit to an aqueous phosphate solution. Many different phosphate solutionsare contemplated as within the scope of the present invention. Onenon-limiting example includes phosphate buffered saline (PBS). PBS maybe prepared in many different ways. Some formulations do not containpotassium, while others contain calcium or magnesium. Generally, PBScontains the following constituents: 137 mM NaCl, 2.7 mM KCl, 10 mMsodium phosphate dibasic, 2 mM potassium phosphate monobasic and a pH of7.4. Another non-limiting example is a 0.25 M K₂PO₄ solution. Non-salinephosphate solutions may be prepared using monosodium phosphate(NaH₂PO₄), disodium phosphate (Na₂HPO₄), and water, with phosphoric acidor sodium hydroxide to adjust the pH as desired. Other concentrationsand types of aqueous phosphate solutions are contemplated as within thescope of the invention.

Porosity may be determined by a number of methods well known in the art,however the preferred method is nitrogen absorption. These particles arepreferably not biodegradable. A biodegradable particle will, not bepresent in the body after 2, 4, or preferably 6 months.

Strontium

Conversion of the strontium borate glass results, at the molecularlevel, in a high surface-area porous material, that itself, is anagglomeration containing the strontium phosphate compound. The pores ofthe surface provide access to the strontium phosphate compound. When aradioisotope is mixed with the microparticles, a strong chemical bond ismade with the exposed strontium phosphate compound. Without being heldto any particular chemical reaction or theory, it is believed that theisotope can bind in a substitution reaction removing a phosphate [PO₄group], or it may be bound into a void space or it may substitute for astrontium ion [Sr+²].

Microparticle Size and Shape

By manufacturing a non-radioactive solid strontium-containing borateglass microparticle of a specific diameter, the size and shape of thestrontium phosphate microparticle can be controlled; conversion resultsin a porous strontium phosphate microparticle of a specific diameter.Since the starting material is a solid strontium-containing borate glassmicroparticle and it becomes fully (or partially) converted to a porousstrontium phosphate microparticle, the physical parameters of shape,size, diameter are dictated by the glass microparticle manufacturingprocess. Importantly, the size and dimension of the converted strontiummicroparticle are substantially the same as the size and dimension ofthe starting strontium borate glass microparticle. This feature providesthe significant advantage of being able to control the size anddimension of the delivery vehicle itself, the porous strontium phosphatemicroparticle.

“Microparticle”, as used herein, generally refers to a particle of arelatively small size, but not necessarily in the micron size range; theterm is used in reference to particles of sizes that can be less than 50nm to 1000 microns or greater. “Radiomicroparticle” refers to themicroparticles of the present invention with one or more radioisotopesadsorbed thereon. The microparticles are preferably round spheroidshaving a preferred diameter of about 20 μm and above. In other preferredembodiments, the microparticles range from about 20 μm to about 200 μm,from about 30-80 μm, from about 20-40 μm, and from about 25 μm to 38 μm.In another embodiment, the diameter of the particles is from about 5 toabout 100 microns, preferably from about 10 to about 50 microns. As usedherein, the microparticle encompasses microspheres, microcapsules,ellipsoids, fibers, and microparticles, unless specified otherwise.

Customized Delivery

The porosity of the resulting strontium phosphate material and thecontrollable size and number of the microparticles provide an excellentdelivery platform for delivering radiation to specific locations.

Importantly, no radioisotope is incorporated in the borate glassmicroparticle. Thus, the process of manufacturing of the microsphere hasbeen divorced from the process of adding the radioisotope label or theradiotherapeutic. Prior radiomicrospheres must be manufactured as glassor biopolymer particles with the radioisotope as a homogeneous integralcomponent of the glass or biopolymer. The present inventive approachprovides a medical radiology professional the ability to control theradiodiagnostic and radiotherapeutic regimen by allowing them, in theclinical setting, to decide the type and quantity ofradiopharmaceutical(s) to incorporate into the delivery vehicle. Some ofthe advantages of this approach include the ability to customize thedose to the patient, customize imaging of the tissue, reducingtime-related degradation of the activated radiopharmaceutical, andreducing exposure to medical personnel.

Delivery of Multiple Isotopes

The combination of the significantly increased surface area and theelectrical attraction of the radioisotope to the porous microparticleprovides for bonding multiple radioisotopes to the microparticle. Inpreferred embodiments, two radioisotopes are bound. Binding a firstisotope to the porous microparticle is performed using simple mixing inan appropriate solution over a pre-determined time, and then washing andeluting out the unbound isotope. This provides a composition where aradioisotope is bound to the microparticles.

Binding a second isotope to the porous microparticle is performed bysimple mixing in a solution having the second isotope. Importantly, thesecond isotope does not displace the first isotope since themicroparticles have a large surface area, and a nuclear pharmacist orother professional can take advantage of the different bindingcapacities of various radioisotopes to the microparticles. Thus, threeand even four different radioisotopes can be bound within a single dose,or batch, of microparticles.

Method of Treatment

The invention also provides a method of administeringstrontium-phosphate radiomicroparticles to a patient in need thereof,comprising delivering, for example by catheter or injection, to a tissuetarget or organ of the patient, a composition comprisingstrontium-phosphate radio microparticles and a physiologicallyacceptable carrier.

In one preferred embodiment, the method is a method of treatment of atumor, particularly a hyper vascular tumour. Such treatments, asdescribed further below, may be by delivery into a blood vessel such asto lodge the particles in the vasculature (radio embolization) or bydirect injection into the site. Radiomicroparticles of the invention foruse in such treatments are also provided by the invention.

In other preferred methods, there are provided additional featuresavailable singularly and in combination.

In one preferred method, the tissue target or organ is selected from thegroup consisting of: brain, myocardium, thyroid, lung, liver, spleen,gall bladder, kidney, bone, blood, and head and neck, prostate, breast,ovarian and uterine.

Diagnosis

The invention also provides a method of obtaining a radiologic image ofa tissue or organ of a patient, comprising administering to a tissuetarget or organ of the patient a composition containingstrontium-phosphate radiomicroparticles, as described herein, andobtaining a radiologic image of the tissue or organ, typically bycapturing the gamma radiation emitted by the radiomicroparticles.

Diagnostic agents comprising the radiomicroparticles of the inventionare thus also provided by the invention.

In this embodiment, the radioisotope is typically a radio diagnosticagent and in one embodiment is preferably Technetium-99m for SPECTimaging and fluorine 18 or Gallium 68 for PET imaging. Typically forthese methods, the radio microspheres will comprise spheres in thebetween about 20 and about 40 microns in diameter.

The radiologic image may be captured using any suitable nuclear imagingtechnique.

Further, by using radiation dosimeters which show the keV peaks ofvarious radioisotopes, activity can be tested, and tailored to aspecific therapy. For example, treatment could in one non-limitingexample consist of 100 units of isotope #1 and 50 units of isotope #2.

Delivery to Tissue

The microparticles may be administered to the patient for example,through the use of catheters either alone or in combination withvasoconstricting agents or by any other means of administration thateffectively causes the microparticles to become embedded in thecancerous or tumor bearing tissue. For purposes of administration, themicroparticles are preferably suspended in a pharmacologicallyacceptable suspension medium. Preferably the suspension medium has asufficient density or viscosity to prevent the microparticles fromsettling out of suspension during the administration procedure.Presently preferred liquid vehicles for suspension of the microparticlesinclude polyvinylpyrrolidone (PVP), (such as that sold under the tradedesignation Plasdone K-30 and Povidone by GAF Corp), one or morecontrast agents, (such as that sold under the trade designationMetrizamide by Nyegard & Co. of Oslo, Norway, or under the tradedesignation Renografin 76 by E. R. Squibb & Co.) and saline, orcombinations thereof. Although many contrast media provide for theadjustment of specific gravity, the addition of specific gravityadjusting components, such as dextrans (e.g. 50% dextran) may also beuseful.

Types of Radioisotopes

In a preferred embodiment of the present invention, theradioisotopes/radionuclides are chosen so that when administered to thepatient, the microparticles may emit alpha, beta or gamma radiation, orprotons or a combination of two or more of these. The alpha or betaemitter is chosen to deliver a therapeutic intensity and therapeuticamount of short-range (e.g., a penetration of the tissue on the order ofabout several millimetres or less) radiation but does not emit asignificant amount of unwanted radiation which could have a negativeimpact on healthy tissue surrounding the cancerous or tumor bearingtissue. The gamma or proton emitter is chosen to deliver a diagnosticintensity and diagnostic amount of longer-range (e.g., capable ofexternal detection) gamma radiation, or protons, but does not emit asignificant amount of unwanted radiation.

Since the radioisotopes/radionuclides may be bonded or prepared in situjust prior to delivery by a radiology professional, the type ofradioisotope(s) may be chosen based on each patient's needs anddiagnosis. By providing a patient-specific dosing, patient outcome isimproved and side-effects are minimized. Patient data such as age,gender, weight, and pre-existing conditions are considered whendetermining a radiotherapeutic and/or radiodiagnostic profile. Cancerdata such as tumor size, tumor type, tumor location, degree of surgicalintervention and success, vascular structures within and adjacent to thearea being treated, and organ involvement are also considered whendetermining a radiotherapeutic and/or radiodiagnostic profile.

The radioisotope Yttrium-90 which form radioisotopes having a half-lifegreater than about two days and less than about 30 days is oneparticularly preferred therapeutic radioisotope which emit therapeuticbeta radiation.

For radioimaging techniques such as SPECT, the radioisotopetechnetium-99m is particularly preferred. For PET imaging Fluorine-18 orGallium-68 are preferred.

The present invention includes wherein the radioisotope isradiopharmaceutical grade and is selected from the group consisting of:Actinium-225, Antimony-127, Arsenic-74, Barium-140, Bismuth-210,Californium-246, Calcium-46, Calciurn-47, Carbon-11, Carbon-14,Cesiurn-131, Cesium-137, Chromium-51, Cobalt-57, Cobalt-58, Cobalt-60,Copper-64, Copper-67, Dysprosium-165, Erbium-169, Fluorine-18,Gallium-67, Gallium-68, Gold-198, Holmium-166, Hydrogen-3, Indium-111,Indium-113m, Iodine-123, Iodine-124, Iodine-125, Iodine-131 Diagnostic,Iodine-131 Therapeutic, Iridium-192, Iron-59, Iron-82, Krypton-81m,Lanthanum-140, Lutetium-177, Molybdenum-99, Nitrogen-13, Oxygen-15,Paladium-103, Phosphorus-32, Radon-222, Radium 223, Radium-224,Rhenium-186, Rhenium-188, Rubidium-82, Samarium-153, Selenium-75,Sodium-22, Sodium-24, Strontium-89, Technetium-99m, Thallium-201,Xenon-127, Xenon-133, Yttrium-90, Zirconium 89, and combinationsthereof.

Where combinations of radioisotopes are used with the microparticles,preferred combinations of radioisotopes include the combination of oneor more beta emitters with one or more gamma emitters. Examples ofpreferred combinations include, but are not limited, to Y-90/In-111Y-90/Tc-99m, Y-90/Ga-68, Y-90/F-18, Y-90/Cu-64, Cu-67/Cu-64,Y-90/Lu-177, P-32/In-111, P-32/Tc-99m, P-32/Ga-68, Ho-166/In-111,Ho-166/Tc-99m, Sm-153/In-II 1, and Sm-153/Tc-99m.

Particularly preferred radioisotopes include Technetium-99m andIndium-111 (radiodiagnostic gamma emitters), Lutetium-177 (being both abeta and gamma emitter), Samarium-153 and Yttrium-90 (radiotherapeuticbeta emitters) and Gallium-68 and fluorine-18 (diagnostic protonemitters), Tc-99m has been used for imaging and function studies of thebrain, myocardium, thyroid, lungs, liver, gallbladder, kidneys, bone,blood, and tumors. Indium-111 pentetreotide has been used in imaging ofneuroendocrine tumors that overexpress somatostatin receptors and hasbecome standard for localization of these tumors. This radio ligand isinternalized into the cell and can induce receptor-specific cytotoxicityby emission of Auger electrons. Lutetium-177 having both gamma and betaproperties enables its use in imaging as well as treatment. It has ashorter radius of penetration that Y-90 which makes it an idealcandidate for radiotherapy of small tumors. Samarium-153 Lexidronam(chemical name Samarium-153-ethylene diamine tetramethylene phosphonate,abbreviated Sarnariurn-153 EDTMP, trade name Quadramet) is a complex ofa radioisotope of the lanthanide element samarium with the chelator EDTMP. It has been used to treat cancer pain when cancer has spread to thebone. Once injected into a vein, it distributes throughout the body andlocalizes in areas where cancer has invaded the bone, allowing the betaparticles (electrons) to destroy the nearby cancer cells. It is alsocommonly used in lung cancer, prostate cancer, breast cancer, andosteosarcoma. Yttrium-90 has been used in the treatment of variouscancers including lymphoma, leukaemia, ovarian, colorectal, pancreatic,and bone cancers, and in treatment of rheumatoid arthritis byradionuclide synovectomy.

Although an attempt is made to provide an exhaustive list, it iswell-known to nuclear medicine specialists that radioisotopes may beproduced using a generator system like Mo—Tc or Sn/In systems, a thermalneutron reactor, a cyclotron, or fission produced. Accordingly, anyradioisotopes with:functional equivalents to those listed are intendedto be encompassed wherever appropriate within the scope of the presentinvention.

Glass Preparation

The strontium containing borate glass microspheres described hereinrepresent a further aspect of the present invention. These microspheresare preferably not biodegradable. The microparticles of the presentinvention may be prepared from a homogenous mixture of powders (i.e.,the batch) that is melted to form the desired glass composition. Theexact chemical compounds or raw materials used for the batch is notcritical so long as they provide the necessary oxides in the correctproportion for the melt composition being prepared. For instance, formaking a strontium borate glass, then strontium, borate, and/or soda,powders may be used as some the batch raw materials.

Typically the strontium containing borate glass will comprise 10 or moremol % strontium oxide, but preferably 15 mol % or greater. The strontiumcontaining borate glass may comprise up to 25 mol % strontium oxide, butmore preferably 20±5 mol % strontium oxide.

The present invention therefore provides a strontium containing borateglass microsphere, comprising 10 or more mol % strontium oxide andhaving a diameter of between 5 and 1000 microns.

Typically the strontium containing borate glass will comprise 10 mol %or more sodium oxide, preferably 15 mol % or more. Preferably thestrontium containing borate glass will comprise up to 30 mol % sodiumoxide. Preferably the strontium containing borate glass will comprise20±5 or 20±10 mol % sodium oxide. Up to one quarter of the sodium oxideportion of the glass may be replaced by lithium oxide or potassium oxide(or a combination of the two).

Typically the strontium containing borate glass will comprise at least50% boron oxide, preferably the strontium containing borate glass willcomprise at least 60% boron oxide, preferably the strontium containingborate glass will comprise up to 70% boron oxide. Preferably thestrontium containing borate glass will comprise 60±10 mol % boron oxide.

Typical compositions suitable for preparing the batch are given below,although it is to be understood that these should not be considered tobe limiting; starting glasses having a wide range of compositions can beused so long as they contain a source of strontium oxide (from theglass) and phosphate, which may be from the starting glass or may bepresent in the solution in which the glass is being reacted. The generalcompositions given below assume that the starting glass composition isbeing reacted in a solution that is the source of phosphate to form thestrontium phosphate particle.

A typical composition comprises:

20±10 mol % Na₂O which may contain up to 25% of Li₂O or K₂O or acombination thereof, on a molar basis,

20±5 mol % SrO, up to one quarter of which may be substituted by analternative radiopaque oxide, such as barium, calcium manganese orcobalt oxides.

60±10 mol % B₂O₃; and

0-5 mol % of other oxides.

An example composition is 20:20:60 mol % Na₂O:SrO:B₂O₃.

Thus the composition can be modified by varying the soda content by upto plus/minus 5 or 10 mol %, and or the boron oxide content byplus/minus 10 mol %. It is also possible to substitute up to 5 mol %Li₂O or K₂O (or a combination of the two) for a portion of the soda. Itis also possible to substitute small amounts of P₂O₅ (say up to 5 mol %)for a portion of the B₂O₃. A few (up to 5) mol % of a wide range ofother oxides can be substituted into the base glass composition forvarious specific purposes such as varying the melting temperature or theconversion reaction rate, modifying the radio-opacity, etc. If needed,the SrO could be replaced partially (up to 5 mol % of the 20) by bariumoxide, calcium oxide, manganese oxide or cobalt oxide (eg CO) or acombination thereof.

All percentages herein are mol % unless indicated or inherentlyotherwise. While the materials are described as containing variousoxides and other components by molar %, those skilled in the artunderstand that in the final glass or crystalline composition, thecompounds are dissociated, and the specific compounds are not separatelyidentifiable or even necessarily separately present. Nonetheless, it isconventional in the art to refer to the final composition as containinga given % of the individual compounds, so that is done here. So fromthis perspective, the compositions herein are on an equivalent basis.

The purity of each raw material is preferably greater than 99.9%. Aftereither dry or wet mixing of the powders to achieve a homogeneousmixture, the mixture may be placed in a platinum crucible for melting.High purity alumina crucibles can also be used if at least small amountsof alumina can be tolerated in the glass being made. The cruciblescontaining the powdered batch are then placed in an electric furnacewhich is heated 1000° C. to 1600° C., depending upon the composition. Inthis temperature range, the batch melts to form a liquid which isstirred several times to improve its chemical homogeneity. The meltshould remain at 1000° C. to 1600° C., until all solid material in thebatch is totally dissolved, usually 4-10 hours being sufficient.Significantly, by not incorporating the radioisotope into the melt, noradioisotope can be vaporized, thus avoiding a radiation hazard.

Another advantage of the invention is the ability to use radioisotopesthat have a shorter half-life. For example, Tc-99m (Technetium-99m)cannot be made part of the glass, i.e. the half-life may often be tooshort to be useful when it is incorporated as part of certainhomogeneous glass-radioisotope compositions. Additionally, the abilityto use radioisotopes that would otherwise be destroyed or degrade by theglass-melt process. For example, trying to incorporate Technetium orRhodium into a melt would vaporize the Technetium or Rhodium.

When melting and stirring is complete, the crucible is removed from thefurnace and the melt is quickly quenched to a glass by pouring the meltonto a cold steel plate or into clean, distilled water. This procedurebreaks the glass into fragments, which aids and simplifies crushing theglass to a fine powder. The powder is then sized and spheroidized foruse.

Spheroidizing

To obtain spheroid microparticles having a diameter in the desired rangeof micrometres, the glass is processed using varying techniques such asgrinding and passing through mesh sieves of the desired size, where theglass particles may be formed into spheroids by passing the sizedparticles through a gas/oxygen flame where they are melted and aspherical liquid droplet is formed by surface tension. A vibratoryfeeder located above the gas/oxygen burner slowly vibrates the powderinto a vertical tube that guides the falling powder into the flame at atypical rate of 5-25 gm/hr. The flame is directed into a metal containerwhich catches the spheroidized particles as they are expelled from theflame. The droplets are rapidly cooled before they touch any solidobject so that, their spherical shape is retained in the solid product.

After spheroidization, the glass spheres are preferably collected andrescreened based upon size. As a non-limiting example, when themicroparticles are intended to be used in the treatment of liver cancer,the fraction less than 30 and greater than 20 micrometres in diameter isrecovered since this is a desirable size for use in the human liver.After screening, the −30/+20 microparticles are examined with an opticalmicroscope and are then washed with a weak acid (HCl, for example),filtered, and washed several times with reagent grade acetone. Thewashed spheres are then heated in a furnace in air to 500-600° C. for2-6 hours to destroy any organic material.

The final step is to examine a representative sample spheres in ascanning electron microscope to evaluate the size range and shape of thespheres. The quantity of undersize spheres is determined along with theconcentration of non-spherical particles. The composition of the spherescan be checked by energy dispersive x-ray analysis to confirm that thecomposition is correct and that there is an absence of chemicalcontamination.

The glass microparticles are then ready for phosphate conversion,bonding with radionuclide, and subsequent administration to the patient.

In accordance with the present invention, the above processing steps aremerely exemplary and do not in any way limit the present invention.Similarly, the present invention is not limited to glass microparticleshaving a size described above; the size of the microparticles of thepresent invention may be varied according to the application.

Types of Cancers

The microparticles of the present invention may be used in a variety ofclinical situations for which internal radiation therapy is indicated.These include, for example the treatment of Tumors and the treatment ofarthritis.

The treatment of both benign and cancerous tumors is contemplated.Tumors may be treated, for example, by selective internal radiationtherapy (SIRT) for i.a. hypervascular tumors or other tumors of areasthat have favorable vasculature, including the liver (liver tumorsinclude, for example, hepatocellular carcinomas or metastatic diseasearising from other tissues, such as colorectal cancers), spleen, brain,kidney, head & neck, uterine, ovarian and prostate. The microparticlesmay also be used for imaging, including a Liver/Spleen Scan—for tumors,cysts or hepatocellular disease; a Brain Scan—for tumors, trauma, ordementia; a Tumor Scan for malignant tumors or metastatic disease of theKidney, Head & Neck, Uterine/Gynaecologicals; and any Scan or Therapyhaving favorable vasculature for this approach.

One radionuclide imaging technique contemplated as within the scope ofthe invention is single photon emission computed tomography (SPECT) afurther technique contemplated is PET.

Since most organs, besides the liver, have only one blood vessel thatfeeds it, administration may be performed by delivery to that mainfeeder artery and allowing the microparticles to lodge in the capillarybed since they are too large to move through the capillary. The livermay require a specialized delivery regimen. In another embodiment, thevessel that feeds the tumor may be identified, and this artery is usedto deliver the microparticles in a more local fashion.

EXAMPLES Example 1 Preparation of Strontium Phosphate Microspheres

Strontium containing borate glass microspheres were prepared from abatch comprising 20 mol % Na₂O, 20 mol % SrO and 60 mol % Ba₂O₃ asdescribed above. The microspheres ranged in size from 44 to 105 microns.

The microspheres were reacted with 0.25 molar K₂HPO₄ solution (pH=12)for 1 h, 6 h, and 72 hrs at 85° C. After rinsing and drying, the surfacearea was measured by nitrogen absorption using a Micromeretics Tristar3000 device. Multiple samples were measured and averaged. The measuredsurface area was 10, 93, and 72 m²/gm, respectively.

Example 2 Loading Strontium Phosphate Microspheres with Radioisotopes

A solution of 5 ug yttrium (Y-90) chloride in 0.5 ml of 0.05N HCl wasadded to 15 mg of microspheres and incubated for 30 minutes. The amountof yttrium loaded into the microspheres was determined at 1, 5 and 30minutes in 5 replicates and averaged. Up-take of the yttrium with timeis shown in FIG. 1.

As various changes could be made in the above methods and products,without departing from the scope of the invention, it is intended thatall matter contained in the above description or shown in anyaccompanying drawings shall be interpreted as illustrative and not in alimiting sense. Any references recited herein are incorporated herein intheir entirety, particularly as they relate to teaching the level ofordinary skill in this art and for any disclosure necessary for thecommoner understanding of the subject matter of the claimed invention.It will be clear to a person of ordinary skill in the art that the aboveembodiments may be altered or that insubstantial changes may be madewithout departing from the scope of the invention. Accordingly, thescope of the invention is determined by the scope of the followingclaims and their equitable equivalents.

1. A radio microparticle comprising: crystalline strontium phosphate and at least one radioisotope suitable for radio imaging and/or radiotherapy bonded or adsorbed to the surface thereof,
 2. The radio microparticle of claim 1, having a surface area of greater than about 90 square meters per gram.
 3. The radio microparticle of claim 1 which is a microsphere.
 4. The radio microparticle of claim 2 having a diameter of 5 μm to 1000 μm.
 5. The radio microparticle of claim 1, wherein the radioisotope bonded or adsorbed to the surface is a therapeutic alpha or beta-emitting radioisotope.
 6. The radio microparticle of claim 1, wherein the radioisotope bonded or adsorbed to the surface is a diagnostic positron or gamma-emitting radioisotope.
 7. The radio microparticle of claim 1, wherein the radioisotope bonded or adsorbed to the surface comprises a combination of a therapeutic alpha or beta-emitting radioisotope and a diagnostic gamma or positron-emitting radioisotope.
 8. The radio microparticle of claim 1, wherein the radioisotope bonded or adsorbed to the surface is Technetium-99m.
 9. The radio microparticle of claim 1, wherein the radioisotope bonded or adsorbed to the surface is selected from the group consisting of Technetium-99m, Indium-111, Lutetium-177, Samarium-153, Yttrium-90, Holmium-166, Gallium-68, Fluorine-18 and combinations thereof.
 10. The radio microparticle of claim 1, having at least two different radioisotopes bonded or adsorbed to the surface
 11. (canceled)
 12. A process for the preparation of a radio microparticle, comprising: (i) reacting a strontium-containing borate glass microparticle with a phosphate solution such as to convert at least a portion of the strontium-containing borate glass to crystalline strontium phosphate; and (ii) bonding or adsorbing at least one radioisotope suitable for radio imaging and/or radiotherapy to said strontium phosphate microparticle.
 13. A process according to claim 12 wherein the radioisotope is bonded or adsorbed to the surface of the microparticle by contacting the microparticle with a solution of the radioisotope.
 14. A process according to claim 12, wherein the radioisotope is selected from the group consisting of Technetium-99m, Gallium 68, Holmium-166, Fluorine-18, Indium-111, Yttrium-90, Lutetium-177, Samarium-153, and combinations thereof.
 15. A method of administering a radio microparticle to a patient in need thereof, comprising: locally delivering the radio microparticle in a physiologically acceptable carrier to a tissue target or organ of the patient, wherein the radio microparticle comprises crystalline strontium phosphate and at least one radioisotope suitable for radio imaging and/or radiotherapy bonded or adsorbed to the surface thereof.
 16. The method of claim 15 wherein the microparticle is a microsphere.
 17. The method of claim 15 wherein the crystalline strontium phosphate microparticles have a surface area of greater than 90 square meters per gram.
 18. The method of any of claim 15 wherein the radioisotope bonded or adsorbed to the surface is a radio diagnostic agent.
 19. The method of any of claim 15 wherein the radioisotope bonded or adsorbed to the surface is a radio therapeutic agent.
 20. The method of claim 15, wherein the radioisotope bonded or adsorbed to the surface comprises a radio diagnostic agent and a radio therapeutic agent. 21-24. (canceled)
 25. A method of obtaining a radiologic image of a tissue or organ of a patient, comprising: administering a radio microparticle in a physiologically acceptable carrier to a tissue target or organ of the patient, and obtaining the radiologic image of the tissue or organ of the patient; wherein the radio microparticle comprises crystalline strontium phosphate and at least one radioisotope suitable for radio imaging bonded or adsorbed to the surface thereof, 26-37. (canceled) 